Acid-group-substituted diphenylazetidinones process for their preparation, medicaments comprising these compounds, and their use

ABSTRACT

One embodiment of the invention relates to compounds of the formula I:  
                 
in which R1, R2, R3, R4, R5 and R6 have the meanings given in the specification. Other embodiments of the invention relate to physiologically acceptable salts of the compounds of formula I, to processes for their preparation and to medicaments comprising these compounds. The compounds of the invention are suitable for use, for example, as hypolipidemics.

This application claims the benefit of the filing dates of German PatentApplication Number 10227508.4, filed on Jun. 19, 2002, and U.S.Provisional Application No. 60/418,678, filed on Oct. 15, 2002, whichapplications are hereby incorporated by reference.

One embodiment of the invention relates to acid-group-substituteddiphenylazetidinones, their physiologically acceptable salts andderivatives having physiological functions.

Diphenylazetidinones (such as, for example, ezetimibe) and their use fortreating hyperlipidemia, arteriosclerosis and hypercholesterolemia havealready been described [cf. Drugs of the Future 2000, 25(7):679-685 andU.S. Pat. No. 5,756,470].

One embodiment of the invention provides compounds having atherapeutically utilizable hypolipidemic action. For example, oneembodiment of the invention relates to novel compounds which,compared-to the compounds described in the prior art, are absorbed to avery low extent. Very low absorption is to be understood as meaning anintestinal absorption of less than about 10%, for example less than orequal to about 5%.

In one embodiment, absorption of the novel compounds of the inventionmay be less than that of ezetimibe.

In general, pharmaceutically active compounds that are absorbed to a lowextent may have considerably fewer side-effects.

Accordingly, the invention relates to compounds of the formula (I)

wherein

-   -   R1, R2, R3, R4, R5, and R6, independently of one another, are        chosen from:        -   (C₀-C₃₀)-alkylene-(LAG)_(q); or        -   (C₀-C₃₀)-alkylene-(LAG)_(q) wherein at least one carbon atom            of the alkylene radical is replaced by a radical chosen            from: —S(O)_(m)— (wherein m=0-2), —O—, —(C═O)—, —(C═S)—,            —CH═CH—, —C≡C—, —N((C₁-C₆)-alkyl)-, —N(phenyl),            —N((C₁-C₆)-alkyl-phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— and —NH—;            or        -   H, F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)-alkyl,            CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂,            (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, or            O—(C₁-C₆)-alkyl, wherein the alkyl radical is unsubstituted            or at least one hydrogen in the alkyl radical is replaced by            fluorine;        -   C(═NH)(NH₂), PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl,            SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl,            SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl, SO₂—(C₁-C₆)-alkyl, or            SO₂—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl            radical is unsubstituted or substituted one or two times,            each substituent chosen independently from: F, Cl, Br, OH,            CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂;            or        -   NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NH(C₁-C₇)-acyl,            phenyl, or O—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein            the phenyl ring is unsubstituted or substituted one, two, or            three times, each substituent chosen independently from: F,            Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,            (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,            SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂;        -   wherein (LAG) is —(CH₂)₀₋₁₀—SO₃H; —(CH₂)₀₋₁₀—P(O)(OH)₂,            —(CH₂)₀₋₁₀—O—P(O)(OH)₂, or —(CH₂)₀₋₁₀—COOH and wherein q is            1-5; and    -   wherein at least one of the radicals R1 to R6 must have the        meaning (C₀-C₃₀)-alkylene-(LAG)_(q); or        (C₀-C₃₀)-alkylene-(LAG)_(q), wherein at least one carbon atom of        the alkylene radical is replaced by a radical chosen from:        —S(O)_(m)— (wherein m=0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—,        —C≡—C—, —N((C₁-C₆)-alkyl)-, —N(phenyl)-,        —N((C₁-C₆)-alkyl-phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— and —NH—,

or a pharmaceutically acceptable salt thereof, in any stereoisomericform, or a mixture of any such compounds in any ratio;

with the proviso that the compound is not2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonicacid, or a compound wherein the radicals R1-R6 have the meaning—O—(CH₂)₁₋₁₀—COOH, (C₁-C₆)-alkylene-COOH or —COOH.

In one embodiment of the invention, at least one of the radicals R1 toR6 in the compounds of the formula I has the meaning:(C₀-C₃₀)-alkylene-(LAG)_(q); or (C₀-C₃₀)-alkylene-(LAG)_(q), wherein atleast one carbon atom of the alkylene radical is replaced by —O—,—(C═O)—, —N((C₁-C₆)-alkyl), —N(CO—(CH₂)₁₋₁₀—COOH)— or —NH—.

In another embodiment of the invention, one of the radicals R1 or R3 inthe compounds of the formula I has the meaning (C₀-C₃₀)-alkylene-(LAG);or (C₀-C₃₀)-alkylene-(LAG), wherein at least one carbon atom of thealkylene radical is replaced by —O—, —(C═O)—, —N(CH₃)—, or —NH—.

In another embodiment of the invention, one of the radicals R1 or R3 inthe compounds of the formula I has the meaning—(CH₂)₀₋₁—Y—W—(C₀-C₂₅)-alkylene—Y′—W′—(LAG); or—(CH₂)₀₋₁—Y—W—(C₀-C₂₅)-alkylene-Y′-W′-(LAG), wherein at least one carbonatom of the alkylene radical is replaced by an oxygen atom and wherein Yand W independently of one another are chosen from: NH, NCH₃, C═O, O, abond, and S(O)_(m), (wherein m=0-2), and wherein Y′ and W′ independentlyof one another are chosen from: NH, NCH₃, C═O, O, a bond, and S(O)_(m),wherein m=0-2, or Y—W or Y′—W′ in each case, together represent a bond.

In another embodiment of the invention, the group LAG in any of theradicals R1 to R6 in the compounds of the formula I is a carboxylic acidradical or a sulfonic acid radical.

Other than in the operating examples, or where otherwise indicated, allnumbers expressing quantities of ingredients, reaction conditions, andso forth used in the specification and claims are to be understood asbeing modified in all instances by the term “about.” Accordingly, unlessindicated to the contrary, the numerical parameters set forth in thepresent specification and attached claims are approximations that mayvary depending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contain certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements.

Owing to their increased solubility in water, pharmaceuticallyacceptable salts are often more suitable for medical applications thanthe parent compounds. These salts generally have a pharmaceuticallyacceptable anion or cation. Examples of suitable pharmaceuticallyacceptable acid addition salts of the compounds according to theinvention include salts of inorganic acids, such as hydrochloric acid,hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid,sulfonic acid and sulfuric acid; and of organic acids, such as aceticacid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonicacid, fumaric acid, gluconic acid, glycolic acid, isothionic acid,lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonicacid, succinic acid, p-toluenesulfonic acid, tartaric acidand-trifluoroacetic acid. An example of an acceptable salt of thecompounds of the invention is the chloride salt. Examples of suitablepharmaceutically acceptable basic salts include ammonium salts, alkalimetal salts (such as sodium and potassium salts) and alkaline earthmetal salts (such as magnesium and calcium salts).

The scope of the invention also includes salts having a pharmaceuticallyunacceptable anion, which salts may be useful intermediates forpreparing or purifying pharmaceutically acceptable salts and/or for usein nontherapeutic, for example in vitro, applications.

Here, the term “derivative having physiological function” refers to anyphysiologically acceptable derivative of a compound according to theinvention, for example an ester, that is able, upon administration to amammal, for example a human, to form such a compound or an activemetabolite (directly or indirectly).

A further aspect of this invention includes prodrugs of the compoundsaccording to the invention. Such prodrugs can be metabolized in vivo togive a compound according to the invention. These prodrugs may or maynot be active in their own right.

The compounds according to the invention can also be present in variouspolymorphic forms, for example as amorphous and crystalline polymorphousforms.

Accordingly, another aspect of the invention includes the polymorphicforms of the compounds according to the invention.

Hereinbelow, all references to “compound(s) of the formula (I)” refer toa compound or compounds of the formula (I) as described above, and totheir salts, solvates and derivatives having physiological function, asdescribed herein.

The compounds of the formula I and their pharmaceutically acceptablesalts and derivatives having physiological function are usefulmedicaments for treating an impaired lipid metabolism, for examplehyperlipidemia. The compounds of the formula I are also suitable formodulating the serum cholesterol concentration and for preventing andtreating arteriosclerotic manifestations.

As used herein, treating or treatment includes the treating of, forexample, a patient inflicted with a disease or condition, as well as theprevention, prophylaxis, or protective treatment of a patient. Treatmentalso includes treating a subject susceptible to or predisposed todeveloping a disease or condition, which could include patients in whomthe disease or condition has not yet presented, as well as patients inwhom the disease has been successfully treated but could redevelop orreoccur.

The compound(s) of the formula (I) can also be administered incombination with other active compounds.

The amount of a compound of the formula (I) required to achieve thedesired biological effect depends on a number of factors, for example onthe specific compound chosen, on the intended use, on the mode ofadministration and on the clinical condition of the patient. In general,the daily dose is in the range from 0.1 mg to 100 mg (typically from 0.1mg to 50 mg) per day per kilogram of bodyweight, for example 0.1-10mg/kg/day. Tablets or capsules may contain, for example, from 0.01 to100 mg, typically from 0.02 to 50 mg. In the case of pharmaceuticallyacceptable salts, the abovementioned weight data relate to the weight ofthe diphenylazetidinone-ion derived from the salt. An effective amountof a compound of the invention is an amount sufficient to bring about adesired effect. For example, in the context of treating an impairedlipid metabolism, for instance hyperlipidemia, an effective amount of acompound of the invention would constitute an amount sufficient to bringabout a beneficial change in the condition of the patient. For theprophylaxis or therapy of the abovementioned conditions, the compoundsof the formula (I) can be used by themselves, but they may also bepresent in the form of a pharmaceutical composition with an acceptablecarrier. The carrier must of course be acceptable in the sense that itis compatible with the other constituents of the composition andrelatively speaking is not harmful to the health of the patient. Thecarrier can be a solid or a liquid or both and may be formulated withthe compound as an individual dose, for example as a tablet, which cancontain from 0.05% to 95% by weight of the active compound. Furtherpharmaceutically active substances can also be present, includingfurther compounds of the formula (I). The pharmaceutical compositionsaccording to the invention can be prepared by one of the knownpharmaceutical methods, which essentially consist in mixing theconstituents with pharmacologically acceptable carriers and/orauxiliaries.

Pharmaceutical compositions according to the invention include thosewhich are suitable for oral or peroral (e.g. sublingual) administration,although the most suitable manner of administration is dependent in eachindividual case on the nature and severity of the condition to betreated and on the type of the compound of the formula (I) used in eachcase. Coated formulations and coated delayed-release formulations arealso included in the scope of the-invention, as are acid-resistant andenteric formulations. Examples of suitable enteric coatings includecellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration can be presentin separate units, such as,.for example, capsules, cachets, lozenges ortablets, which in each case contain a specific amount of the compound ofthe formula (I); as a powder or granules; as a solution or suspension inan aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oilemulsion. As already mentioned, these compositions can be preparedaccording to any suitable pharmaceutical method that includes a step inwhich the active compound and the carrier (which can consist of one ormore additional constituents) are brought into contact. In general, thecompositions are prepared by uniform and homogeneous mixing of theactive compound with a liquid and/or finely divided solid carrier, afterwhich the product, if necessary, is shaped. For example, a tablet canthus be prepared by pressing or shaping a powder or granules of thecompound, if appropriate with one or more additional constituents.Pressed tablets can be produced by tableting the compound infree-flowing form, such as, for example, a powder or granules, ifappropriate mixed with a binder, lubricant, inert diluent and/or a(number of) surface-active/dispersing agent(s) in a suitable machine.Shaped tablets can be produced by shaping the pulverulent compoundmoistened with an inert liquid diluent in a suitable machine.

Pharmaceutical compositions suitable for peroral (sublingual)administration include lozenges, which contain a compound of the formula(I) with a flavoring, customarily sucrose and gum arabic or tragacanth;and pastilles, which include the compound in an inert base such asgelatin and glycerol or sucrose and gum arabic.

Other suitable active compounds for the combination preparationsinclude, but are not limited to:

all antidiabetics mentioned in Rote Liste 2001, Chapter 12. They can becombined with the compounds of the formula I according to the inventionto achieve a synergistically enhanced action. The active compoundcombination can be administered either by separate administration of theactive compounds to the patient or in the form of combinationpreparations comprising a plurality of active compounds in a singlepharmaceutical preparation.

Antidiabetics include insulin and insulin derivatives, such as, forexample, Lantuso® or HMR 1964, GLP-1 derivatives, such as, for example,those disclosed by Novo Nordisk A/S in WO 98/08871, and oralhypoglycemic active compounds.

Examples of oral hypoglycemic active compounds include sulfonylureas,biguadines, meglitinides, oxadiazolidinediones, thiazolidinediones,glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassiumchannel openers, such as, for example, those disclosed by Novo NordiskA/S in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors ofliver enzymes involved in stimulating gluconeogenesis and/orglycogenolysis, modulators of glucose uptake, compounds which modulatelipid metabolism, such as antihyperlipidemic active compounds andantilipidemic active compounds, compounds that reduce food intake, PPARand PXR agonists and active compounds that act on the ATP-dependentpotassium channel of the beta cells.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an HMGCoA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, or rosuvastatin.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with a cholesterol absorption inhibitor,such as, for example, ezetimibe, tiqueside, or pamaqueside.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with a PPAR gamma agonist, such as, forexample, rosiglitazone, pioglitazone, JTT-501, GI 262570.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with a PPAR alpha agonist, such as, forexample, GW 9578, or GW 7647.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with a mixed PPAR alpha/gamma agonist,such as, for example, GW 1536, AVE 8042, AVE 8134, or AVE 0847.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with a fibrate, such as, for example,fenofibrate, clofibrate, or bezafibrate.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with an MTP inhibitor, such as, forexample, Bay 13-9952, BMS-201038, or R-103757.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with a bile acid absorption inhibitor,such as, for example, HMR 1453.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with a CETP inhibitor, such as, forexample, Bay 194789.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with a polymeric bile acid adsorber,such as, for example, cholestyramine, or colesolvam.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with an LDL receptor.inducer, such as,for example, HMR1171, or HMR1586.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with an ACAT inhibitor, such as, forexample, avasimibe.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with an antioxidant, such as, forexample, OPC-14117.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with a lipoprotein lipase inhibitor,such as, for example, NO-1886.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with an ATP citrate lyase inhibitor,such as, for example, SB-204990.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with a squalene synthetase inhibitor,such as, for example, BMS-188494.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with a lipoprotein(a) antagonist, suchas, for example, Cl-1027 or nicotinic acid.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with a lipase inhibitor, such as, forexample, Orlistat.

In another embodiment of the invention, the compounds of the formula Iare administered in combination with insulin.

In another embodiment, the compounds of the formula I are administeredin combination with a sulfonylurea, such as, for example, tolbutamide,glibenclamide, glipizide or gliclazide.

In another embodiment, the compounds of the formula I are administeredin combination with a biguanide, such as, for example, metformin.

In another embodiment, the compounds of the formula I are administeredin combination with a meglitinide, such as, for example, repaglinide.

In another embodiment, the compounds of the formula I are administeredin combination with a thiazolidinedione, such as, for example,troglitazone, ciglitazone, pioglitazone, rosiglitazone, or the compoundsdisclosed by Dr. Reddy's Research Foundation in WO 97/41097, for example5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In another embodiment, the compounds of the formula I are administeredin combination with an α-glucosidase inhibitor, such as, for example,miglitol or acarbose.

In another embodiment, the compounds of the formula I are administeredin combination with an active compound that acts on the ATP-dependentpotassium channel of beta cells, such as, for example, tolbutamide,glibenclamide, glipizide, gliazide or repaglinide.

In another embodiment, the compounds of the formula I are administeredin combination with more than one of the abovementioned compounds, forexample in combination with a sulfonylurea and mefformin, a sulfonylureaand acarbose, repaglinide and metformin, insulin and a sulfonylurea,insulin and mefformin, insulin and troglitazon, insulin and lovastatin,etc.

In a further embodiment, the compounds of the formula I are administeredin combination with CART agonists, NPY agonists, MC3 and MC4 agonists,orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BPantagonists, urocortin agonists, β3-agonists, MCH(melanine-concentrating hormone) antagonists, CCK agonists, serotoninreuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HTagonists, bombesin agonists, galanin antagonists, growth hormone, growthhormone-releasing compounds, TRH agonists, decoupling protein 2 or 3modulators, leptin agonists, DA agonists (bromocriptine, doprexin),lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-βagonists.

In one embodiment of the invention, the further active compound isleptin.

In another embodiment, the further active compound is dexamphetamine oramphetamine.

In another embodiment, the further active compound is fenfluramine ordexfenfluramine.

In another embodiment, the further active compound is sibutramine.

In another embodiment, the further active compound is Orlistat.

In another embodiment, the further active compound is mazindol orphentermine.

In another embodiment, the compounds of the formula I are administeredin combination with fiber, for instance insoluble fiber, such as, forexample, Caromax®.

The combination with Caromax® can be administered in a singlepreparation or by separate administration of compounds of the formula Iand Caromax®. Here, Caromax® can also be administered in the form offood, such as, for example, in bakery goods or muesli bars. Compared tothe individual active compounds, the combination of compounds of theformula I with Caromax® is, in addition to providing an enhanced action,also characterized by its improved tolerability, for example withrespect to the lowering of LDL cholesterol.

It goes without saying that each suitable combination of the compoundsaccording to the invention with one or more of the compounds mentionedabove and optionally one or more further pharmacologically activesubstances is included in the scope of the present invention.

The scope of the invention also includes both, stereoisomer mixtures ofcompounds of the formula I and the pure stereoisomers of the formula I,as well as diastereomer mixtures of the compounds of formula I and thepure diastereomers. The mixtures may, for example, be separated by knownchromatographic means.

One embodiment of the invention includes both racemic andenantiomerically pure compounds of the formula I of the followingstructure:

Examples of amino protective groups that can be used include thebenzyloxycarbonyl (Z) radical, which can be removed by catalytichydrogenation; the 2-(3,5-dimethyloxyphenyl)propyl(2)oxycarbonyl(Ddz) ortrityl (Trt) radical, which can be removed by weak acids; thet-butylcarbamate (BOC) radical, which can be removed by 3M hydrochloricacid; and the 9-fluorenylmethyloxycarbonyl (Fmoc) radical, which can beremoved using secondary amines.

Another embodiment of the invention relates to a process for preparingdiphenylazetidinone derivatives of formula I.

Y can be S, O, (C═O), (C═S), CH═CH, C≡C, N((C₁-C₆)-alkyl), N(phenyl),N((C₁-C₆)-alkyl-phenyl), N(CO—(CH₂)₁₋₁₀—COOH) or NH;

R11 can be H or, if Y=(C═O) or (C═S), then R11 can be OH;

W, Y′ and W′ can, independently of one another and of Y, be —S(O)_(m)—(where m=0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—, —C≡C—,—N((C₁-C₆)-alkyl)-, —N(phenyl), —N((C₁-C₆)-alkyl-phenyl)-,—N(CO—(CH₂)₁₋₁₀—COOH)— or —NH— or a bond;

x, y and z independently of one another can be 0 to 10.

In compound II, —(CH₂)x-Y—R11 can alternatively also be attached to oneof the other two phenyl rings.

The process for preparing compounds of the formula I comprises reacting,for example, an amine or a hydroxy compound of the formula II with analkylating or acylating agent whichmay carry a further functionality(forexample in the omega position), if appropriate in protected form. Thisfunctionality may be used (after deprotection) for attaching (LAG), forexample with the formation of ether, amine or amide bonds.

The examples below serve to illustrate the invention in more detail,without limiting the invention to the products and embodiments describedin the examples.

EXAMPLE I4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylamino}butane-1-sulfonicacid (6)

a)3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]4-phenyl-oxazolidin-2-one(1)

27 g of3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one, 13.6g of tert-butyldimethylsilyl chloride and 10.2 g of imidazole weredissolved in 36 ml of dimethylformamide and stirred at 60° C. for 90min. After the reaction ended, the mixture was dissolved in ethylacetate and extracted two times with water. The organic phase was driedover magnesium sulfate, filtered and concentrated under reducedpressure. This produced3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-one(1) of molecular weight 471.65 (C₂₆H₃₄FNO₄Si); MS (ESI): 340.28(MH⁺−HOSi(CH₃)₂C(CH₃)₃).

b)4-[5-(tert-butyidimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile(2)

16.2 g of3-[5-(tert-butyidimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-onewere dissolved in 350 ml of dichloromethane. 19.8 ml of Hünig base and10.14 g of 4-[(4-methoxyphenylimino)methyl]benzonitrile were added, andthe solution was cooled to −10° C. 8.52 ml of trimethylsilyl triflatewere added to the cooled solution, and the mixture was stirred at −10°C. for 30 min. The solution was then cooled to −30° C., and 44 ml oftitanium tetrachloride solution were added. The reaction mixture wasstirred at a temperature ranging from −30 to 40° C. for 2 h. Thesolution was then allowed to warm to room temperature and the reactionsolution was washed successively with 200 ml of 2N sulfuric acid, 300 mlof 20% strength sodium hydrogen sulfite solution and sat. sodiumchloride solution. The organic phase was dried over magnesium sulfateand concentrated under reduced pressure.The residue was purified onsilica gel using n-heptane/ethyl acetate 3/1. This produced4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile(2) of molecular weight 707.93 (C₄₁H₄₆FN₃O₅Si); MS (ESI): 590.51(MH⁺−C₇H₅N₂).

c)4-[3-[3-(tert-butyidimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile(3)

13.2 g of4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile(2) were dissolved in 380 ml of methyl tert-butylether. 18.6 ml ofN,O-bis(trimethylsilyl)acetamide and 1.86 ml of a 1 M solution oftetrabutylammonium fluoride in tetrahydrofuran were added and themixture was stirred at room temperature for 2 h. After the reactionended, 10 ml of acetic acid were added, the reaction mixture wasconcentrated under reduced pressure and the residue was purified onsilica gel using toluene/ethyl acetate 50/1. This produced4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile(3) of molecular weight 544.75 (C₃₂H₃₇FN₂O₃Si); MS (ESI): 545.56 (M+H⁺).

d)4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile(4):

3.5 g of4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrilewere dissolved in 65 ml of tetrahydrofuran. 0.74 ml of acetic acid and8.03 ml of a 1 M solution of tetrabutylammonium fluoride intetrahydrofuran were added and the mixture was stirred at roomtemperature for 2 h. Another 4.82 ml of the tetrabutylammonium fluoridesolution were then added, and the mixture was stirred at refluxtemperature for another 3 h. The cooled reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel chromatography using n-heptane/ethyl acetate 2/1. Thisproduced4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile(4) of molecular weight 430.48 (C₂₆H₂₃FN₂O₃); MS (ESI): 431.24 (M+H⁺).

e)1-(4-Aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one(5)

1.22 g of4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrilewere dissolved in 90 ml of ethanol. 10 ml of conc. ammonia solution andan excess of Raney nickel were added, and the mixture was stirred at 60°C. and a hydrogen pressure of 10 bar for 8 h. Overnight, the reactionmixture cooled to room temperature, and the next day, the catalyst wasremoved, the filtrate was concentrated under reduced pressure and theresidue was purified by silica gel chromatography usingdichloromethane/methanol/ammonia solution 10/1/0.1. This produced1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one(5) of molecular weight 434.51 (C₂₆H₂₇FN₂O₃); MS. (ESI): 418.2(MH⁺−NH₃).

4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxo-azetidin-1-yl]benzylamino}butane-1-sulfonicacid (6)

At room temperature, 87 mg of the above benzylamine were dissolved in 3ml of dry acetonitrile, 40 μl of 1,4-butanesultone were added and themixture was heated under reflux for 12 h. The cooled reaction solutionwas concentrated under reduced pressure and purified chromatographically(silica, gel;

dichloromethane/methanol 85/15+10% water). This gives4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylamino}butane-1-sulfonicacid (6) of molecular weight 570.69 (C₃₀H₃₅FN₂O₆S); MS (ESI): 553.28(MH⁺−H₂O).

EXAMPLE II2-[(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butyl)methylamino]ethylsulfonicacid (8)

130 mg of3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one(7) were dissolved in 6 ml of absolute methanol. 120 mg ofN-methyltaurine in 2 ml of water and 60 mg of potassium carbonate werethen added. The mixture was stirred at 50° C. for 24 h. The reactionmixture was concentrated using a rotary evaporator and the residue waspurified by preparative chromatography. Freeze-drying gave the product(50 mg) as an oil.

C₃₂H₃₉FN₂O₇S ESIMS m/z: 614 (M⁺)

EXAMPLE III[2-(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butylamino)ethyl]phosphonicacid (9)

200 mg of3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one(7) were dissolved in 6 ml of absolute methanol. 165 mg of1-aminoethylphosphate and 247 mg of potassium carbonate dissolved in 3ml of water were then added. The mixture was stirred at 90° C. for 8 h.The reaction mixture was concentrated using a rotary evaporator and theresidue was purified by preparative chromatography. Freeze-drying gavethe product (47 mg) as an oil.

C₃₁H₃₈FN₂O₇P ESIMS m/z: 600 (M⁺)

EXAMPLE IV Phosphoric acidmono{6-[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butylamino]hexyl}ester(10)

115 mg of1-(4-fluorofluorophenyl)-3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-4-[4-(2-fluoromethoxyethoxy)phenyl]azetidin-2-one(7) were dissolved in 6 ml of absolute methanol. 130 mg of6-amino-1-hexyl phosphate in 1.5 ml of water and 107 mg of potassiumcarbonate were then added. The mixture was stirred at 70° C. overnight.The reaction mixture was concentrated using a rotary evaporator and theresidue was purified by preparative chromatography. Freeze-drying gavethe product as an oil.

C₃₄H₄₃F₂N₂O₇P ESIMS m/z: 660 (M⁺)

EXAMPLE V4-{4-[3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butane-1-sulfonicacid (12)

160 mg of3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)azetidin-2-one(11) were dissolved in 4 ml of absolute dimethylformamide. 210 mg ofpowdered potassium carbonate and 42 mg of 1,4,-butanesultone were added.The mixture was stirred at room temperature overnight.

The reaction solution was concentrated under oil pump vacuum, taken upin dichloromethane and washed 1× with water. The aqueous phase wasacidified with 2N hydrochloric acid and extracted 2× withdichloromethane. The combined organic phases were dried over sodiumsulfate and concentrated. The residue was chromatographed on a 10 g SiO₂cartridge (dichloromethane/methanol=5/1). The product (72 mg) wasobtained as an oil.

C₂₉H₃₂FNO₇S ESIMS m/z: 557 (M⁺)

EXAMPLE VI4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butane-1-sulfonicacid (13)

250 mg of1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one(7) were dissolved in 6 ml of absolute dimethylformamide. 337 mg ofpowdered potassium carbonate and 69 μl of 1,4, -butanesultone wereadded. The mixture was stirred at room temperature overnight. Thereaction solution was filtered and concentrated under oil pump vacuum.The residue was chromatographed on a 10 g SiO₂ cartridge(dichloromethane/methanol=5/1) and crystallized from diethyl ether. Theproduct (131 mg) was obtained as a solid.

C₂₈H₂₉F₂NO₆S ESIMS m/z: 546 (M⁺)

EXAMPLE VII3-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-oxoazetidin-2-yl}phenoxy)propan-1-sulfoninacid (14)

250 mg of1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one(7) were dissolved in 6 ml of absolute dimethylformamide. 337 mg ofpowdered potassium carbonate and 59 μl of 1,3,-propanesultone wereadded. The mixture was stirred at room temperature overnight. Thereaction solution was filtered and concentrated under oil pump vacuum.The residue was chromatographed on a 10 g SiO₂ cartridge(dichloromethane/methanol=5/1) and crystallized from diethyl ether. Theproduct (250 mg) was obtained as a solid.

C₂₇H₂₇F₂NO₆S ESIMS m/z: 532 (M⁺)

EXAMPLE VIII(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}benzylcarbamoyl)methanesulfonicacid (18)

a)4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-pentyl]-benzonitrile(15)

Under argon, 2.5 g of3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one weredissolved in 30 ml of dichloromethane. 3.9 g of4-[(4-fluorophenylimino)-methyl]-benzonitrile were added and the mixturewas cooled to −10° C. 6.4 ml of diisopropylethylamine and, over a periodof 30 min, 4.05 ml of trimethylsilyl chloride were added to this mixtureso that the temperature did not exceed −5° C. The mixture was stirred atthis temperature for 1 additional hour and then cooled to −25° C. 0.8 mlof titanium tetrachloride were then added slowly. The dark mixture wasstirred at a temperature ranging from −25 to −30° C. overnight and thendecomposed using 35 ml of a 7 percent strength solution of tartaric acidand then stirred at room temperature for another hour. 15 ml of a 20percent strength solution of sodium bicarbonate were then added, and themixture was again stirred for 1 hour. Following magnesium sulfate andconcentrated to about 10 ml. Following the addition of 2 ml ofbistrimethylsilylacetamide, the mixture was heated at reflux for 30 minand then concentrated under reduced pressure. The residue wascrystallized using ethyl acetate/heptane. The product was filtered offwith suction and dried under reduced pressure. This gave the product ofmolecular weight 653.81 (C₃₇H₃₇F₂N₃O₄Si); MS (ESI+): 654.3 (M+H⁺), 582.2(M+H⁺−Si(CH₃)₃).

b){1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile(16)

2 g of4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-pentyl]-benzonitrile(15) were dissolved in 20 ml of methyl-tert-butyl ether and, togetherwith 100 mg of tetrabutylammonium fluoride trihydrate and 1.3 ml ofbistrimethylsilyl acetamide, heated at 40° C. for about 1 h. Thereaction was monitored by thin-layer chromatography. After the reactionended, 0.2 ml of glacial acetic acid was initially added and the mixturewas stirred for 30 min and then concentrated. 20 ml of a mixture ofisopropanol/2N sulfuric acid=10:1 were added to the residue, and themixture was stirred for 1 hour. Following addition of a spatula tip ofsolid sodium bicarbonate, the mixture was again concentrated underreduced pressure, the residue was taken up in ethyl acetate and theorganic phase was washed with water and dried. The residue was, afterremoval of the solvent, purified by column chromatography (SiO₂,CH₂Cl₂/methanol=100:1). This gave the product of molecular weight 418.45(C₂₅H₂₀F₂N₂O₂); MS (DCI+): 419 (M+H⁺).

c)4-(4-Aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one(17)

200 mg of{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile(16) were dissolved in 20 ml of ethanol and, with 0.5 ml of conc.ammonia, hydrogenated over Raney nickel at a hydrogen pressure of 75 barand at 25° C. for 30 hours. The catalyst was filtered off with suction,the mixture was concentrated under reduced pressure and the residue waspurified by column filtration (SiO₂, CH₂Cl₂/methanol/conc.NH₃=100:10:1). This gave the product of molecular weight 422.5(C₂₅H₂₂F₂N₂O₂); MS (DCI+): 423 (M+H+), 405 (M+H⁺−H₂O).

d)(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)methanesulfonicacid (18)

A solution of 120 mg of4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one(17), and 48 μl of diisopropylethylamine in 1 ml of dimethylformamidewas added to a solution of 40 mg of sulfoacetic acid, 110 μl ofdiisopropylcarbodiimide, and 76 mg of hydroxybenzotriazole in 2 ml ofdimethylformamide, and the mixture was stirred at room temperature for12 h. The reaction solution was concentrated and separated by HPLC(Knauer Eurospher-100-10-C18, water (0.1% trifluoroaceticacid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gavethe product of molecular weight 544.58 (C₂₇H₂₆F₂N₂O₆S₁); MS (ESI) 527.10(M+H⁺−H₂O)

EXAMPLE IX{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}methanesulfonicacid (19)

A solution of 60 mg of1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-(4-methoxyphenyl)azetidin-2-one(5) in 1 ml of dimethylformamide was added to a solution of 20 mg ofsulfoacetic acid, 55 μl of diisopropylcarbodiimide, 38 mg ofhydroxybenzotriazole in 1 ml of dimethylformamide, and the mixture wasstirred at room temperature for 12 h. The reaction solution wasconcentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water(0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroaceticacid)=80/20→10/90). This gave the product of molecular weight 556.61(C₂₈H₂₉FIN₂O₇S₁); MS (ESI) 539.05 (M+H⁺−H₂O)

EXAMPLE XN-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}benzyl)succinaminicacid (20)

A solution of 100 mg of4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one(17), and 33 μl of triethylamine in 2 ml of dimethylformamide was addedto a solution of 279 mg of succinic acid, 92 μl ofdiisopropylcarbodiimide, 80 mg of hydroxybenzotriazole in 2 ml ofdimethylformamide, and the mixture was stirred at room temperature for12 h. The reaction solution was concentrated and separated by HPLC(Knauer Eurospher-100-10-C18, water (0.1% trifluoroaceticacid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gavethe product of molecular weight 522.55 (C₂₇H₂₆F₂N₂O₆S₁); MS (ESI) 545.19(M+Na⁺)

EXAMPLE XI{2-[2-({4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}methoxy)ethoxy]ethoxy}aceticacid (21)

A solution of 64 mg of1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-(4-methoxyphenyl)azetidin-2-one(5), and 21 μl of triethylamine in 1 ml of dimethylformamide was addedto a solution of 327 mg of 3,6,9-trioxaundecanedioic acid, 57 μl ofdiisopropylcarbodiimide, 50 mg of hydroxybenzotriazole in 2 ml ofdimethylformamide, and the mixture was stirred at room temperature for12 h. The reaction solution was concentrated and separated by HPLC(Knauer Eurospher-100-10-C18, water (0.1% trifluoroaceticacid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gavethe product of molecular weight 638.70 (C₃₄H₃₉F₁N₂O₉); MS (ESI) 639.27(M+H⁺)

EXAMPLE XII4-((3-Carboxypropionyl)-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzyl}amino)-4-oxobutyricacid (22)

A solution of 70 mg of1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one(5), and 23 μl of triethylamine in 1 ml of dimethylformamide was addedto a solution of 190 mg of succinic acid, 63 μl ofdiisopropylcarbodiimide, 55 mg of hydroxybenzotriazole in 2 ml ofdimethylformamide, and the mixture was stirred at room temperature for12 h. The reaction solution was concentrated and separated by HPLC(Knauer Eurospher-100-10-C18, water (0.1% trifluoroaceticacid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gavethe product of molecular weight 634.4 (C₃₄H₃₅F₁N₂O₉); MS (ESI-neg.)633.22 (M−H⁺)

EXAMPLE XIII11-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}undecanoicacid (23)

A solution of 70 mg of1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one(5), and 23 μl of triethylamine in 1 ml of dimethylformamide was addedto a solution of 371 mg of dodecanedioic acid, 63 μl ofdiisopropylcarbodiimide, 55 mg of hydroxybenzotriazole in 2 ml ofdimethylformamide, and the mixture was stirred at room temperature for12 h. The reaction solution was concentrated and separated byHPLC(Knauer Eurospher-100-10-C18, water (0.1% trifluoroaceticacid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gavethe product of molecular weight 646.81 (C₃₈H₄₇F₁N₂O₆); MS (ESI) 647.35(M+H⁺) TABLE 1 Compounds of the formula I I

Molecular weight of the free base Molecular or acid weight Ex. R1,R2R3,R4 R5,R6 (calculated) (found) XIV

para-F, H para-F, H 531.58 532.4 (MH⁺) XV

para-F, H para-F, H 502.54 503.3 (MH⁺) XVI para-F, H

para-F, H 514.58 515.4 (MH⁺) XVII para-O—CH₃, H

para-F, H 599.68 599.21 (M⁺) XVIII para-O—CH₃, H

para-F, H 739.95 740.42 (MH⁺) XIX para-O—CH₃, H

para-F, H 599.60 600.34 (MH⁺) XX para-O—CH₃, H

para-F, H 534.59 534.4 (MH⁺) XXI

para-F, H para-F, H 578.66 561.25 (MH⁺—H₂O) XXII

para-F, H para-F, H 634.77 617.31 (MH⁺—H₂O) XXIII para-F, H

para-F, H 585.65 567.70 (MH⁺—H₂O) XXIV para-O—CH₃, H

para-F, H 557.64 557.19 (M⁺) XXV

Para-F, H para-F, H 660.70 660.28 (M⁺) XXVI para-O—CH₃, H

para-F, H 600.62 600.24 (M⁺) XXVII para-O—CH₃, H

para-F, H 614.73 597.32 (M—H₂O)⁺¹ XXVIII

para-F, H para-F, H 559,64 560,4 (MH⁺) XXIX

para-F, H para-F, H 545,61 546,3 (MH⁺) XXX

para-F, H para-F, 727,91 710,23 (MH⁺—H₂O) XXXI para-O—CH₃, H

para-F, H 753,93 752,32 (M—H⁺); gemessen im Negativ- modus) XXXII

para-F, H para-F, 573,62 572,09 (M—H+); gemessen im Negativ- modus)XXXIII

para-F, H para-F, H 587,67 586,18 (M—H+); gemessen im Negativ- modus)

Using the method described below, the activity of the compounds of theformula I according to the invention was examined:

Effect of the compounds of the invention on cholesterol absorption and3H-taurocholic acid excretion using fecal excrement of mice, rats orhamsters

NMRI mice, Wistar rats, or Golden Syrian hamsters (in groups of n=4-6)were kept in metabolic cages, where they were fed with a standard diet(Altromin, Lage (Lippe)). The afternoon prior to the administration ofthe radioactive tracers (14C-cholesterol), the feed was removed and theanimals were adapted to grates.

Additionally, the animals were labeled s.c. with 3H-TCA (taurocholicacid) (for example 1 μCi/mouse up to 5 μCi/rat) 24 hours prior to theperoral administration of the test meal (14C-cholesterol in Intralipid®20, Pharmacia-Upjohn).

Cholesterol absorption test: 0.25 ml/mouse Intralipid®D 20(Pharmacia-Upjohn) ((spiked with 0.25 μCi of 14C-cholesterol in 0.1 mgof cholesterol) was administered perorally by gavage.

Test substances were prepared separately in 0.5% methylcellulose(Sigma)/5% Solutol (BASF, Ludwigshafen) or a suitable vehicle.

The administration volume of the test substance was 0.5 ml/mouse. Thetest substance was administered immediately prior to the test meal(Intralipid labeled with 14C-cholesterol) (cholesterol absorption test).

The feces were collected over a period of 24 h. Fecal elimination of14C-cholesterol and 3H-taurocholic acid (TCA) was determined after 24hours.

The livers were removed and homogenized, and aliquots were incineratedin an oximate (Model 307, Packard) to determine the amount of14C-cholesterol that had been taken up/absorbed.

Evaluation

Feces Samples

The total weight was determined, the sample was made up with water to adefined volume and then homogenized, and an aliquot was evaporated todryness and incinerated in an oximate (Model 307 from Packard for theincineration of radioactively labeled samples). The amount ofradioactive 3H-H₂O and 14C-CO₂ was extrapolated to the amount of3H-taurocholic acid and 14C-cholesterol, respectively, that was excreted(dual isotope technique). The ED₂₀₀ values were interpolated from adose-effect curve as those doses at which the excretion of TCA orcholesterol was doubled, based on a control group treated at the sametime.

Liver Samples

The amount of-14C-cholesterol taken up by the liver was based on theadministered dose. The ED50 values were interpolated from a dose-effectcurve as the dose at which the uptake of 14C-cholesterol by the liverwas halved (50%), based on a control group.

The ED50 values below demonstrate the activity of the compounds of theformula I according to the invention Example No. ED₅₀ (liver) [mg/mouse]I 1.0 II >0.1 IV 0.3 VIII 0.3 IX <1.0 X <1.0 XIII <0.1 XVIII 0.005 XXI0.1 XXII 0.1 XXV 0.3 XXVIII 0.3

As can be seen from the table, the compounds of the formula I have verygood cholesterol-lowering action.

Bioabsorption

The bioabsorption of the compounds of the formula I was examined usingthe Caco cell model (A. R. Hilgers et al., Caco-2 cell monolayers as amodel for drug transport across the intestinal mucosa, Pharm. Res. 1990,7, 902).

From the measured data, it can be seen that the bioabsorption of thecompounds of the formula I according to the invention was considerablylower than that of the compounds described in the prior art (referencestructure):

1. A compound of the formula I,

wherein R1, R2, R3, R4, R5, and R6, independently of one another, arechosen from: LAG; or (C₁-C₃₀)-alkyl, wherein the (C₁-C₃₀)-alkyl issubstituted by q LAG units; or (C₁-C₃₀)-alky, wherein the (C₁-C₃₀)-alkylis substituted by q LAG units; and wherein at least one carbon atom ofthe alkylene alkyl radical is replaced by a radical chosen from:—S(O)_(m)— (wherein m═0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—, —C≡C—,—N((C₁-C₆)-alkyl)-, —N(phenyl), —N((C₁-C₆)-alkyl-phenyl)-,—N(CO—(CH₂)₁₋₁₀—COOH)— and —NH—; or H, F, Cl, Br, I, CF₃, NO₂, N₃, CN,COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl,wherein the alkyl radical is unsubstituted or at least one hydrogen inthe alkyl radical is replaced by fluorine; or C(═NH)(NH₂), PO₃H₂, SO₃H,SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl,S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl,SO₂—(C₁-C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, wherein n=0-6, and whereinthe phenyl radical is unsubstituted or substituted one or two times,each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN,OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; and NH₂,NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NHCO(C₁-C₆)-alkyl, phenyl, orO—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl ring isunsubstituted or substituted one, two, or three times, each substituentchosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; wherein (LAG) is—(CH₂)₀₋₁₀—SO₃H; —(CH₂)₀₋₁₀—P(O)(OH)₂, —(CH₂)₀₋₁₀—O—P(O)(OH)₂, or—(CH₂)₀₋₁₀—COOH and wherein q is 1-5; and wherein at least one of theradicals R1 to R6 must have the meaning: LAG; or (C₁-C₃₀)-alky, whereinthe (C₁-C₃₀)-alkyl is substituted by q LAG units; or (C₁-C₃₀)-alky,wherein the (C₁-C₃₀)-alkyl is substituted by q LAG units; and wherein atleast one carbon atom of the alkyl radical is replaced by a radicalchosen from: —S(O)_(m)— (wherein m=0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—,—C—C—, —N((C₁-C₆)-alkyl)-, —N(phenyl)-, —N((C₁-C₆)-alkyl-phenyl)-,—N(CO—(CH₂)₁₋₁₀—COOH)— and —NH—, or a pharmaceutically acceptable saltthereof, in any stereoisomeric form, or a mixture of any such compoundsin any ratio; with the proviso that the compound is not2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonicacid, or a compound wherein the radicals R1-R6 have the meaning—O—(CH₂)₁₋₁₀—COOH, (C₁-C₆)-alkylene-COOH or —COOH.
 2. A compound asclaimed in claim 1, wherein R2, R4, R5, and R6, independently of oneanother, are chosen from: H, F, Cl, Br, I, CF₃, NO₂, N₃, CN,COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂,(C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl,wherein the alkyl radical is unsubstituted or at least one hydrogen inthe alkyl radical is replaced by fluorine; or C(═NH)(NH₂), PO₃H₂, SO₃H,SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl,S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl,SO₂-(C₁-C₆)-alkyl, or SO₂-(CH₂)_(n)-phenyl, wherein n=0-6, and whereinthe phenyl radical is unsubstituted or substituted one or two times,each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN,OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; and NH₂,NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NHCO(C₁-C₆)-alkyl, phenyl, orO—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl ring isunsubstituted or substituted one, two, or three times, each substituentchosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; R1 and R3, independently ofone another, are chosen from: LAG; or (C₁C₃₀)-alkylene-(LAG); or(C₁-C₃₀)-alkylene-(LAG), wherein at least one carbon atom of thealkylene radical is replaced by —O—, —(C═O)—, —N(CH₃)— or —NH—; or H, F,Cl, Br, I, CF₃, NO₂, N₃, CN, COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl, wherein the alkyl radical isunsubstituted or at least one hydrogen in the alkyl radical is replacedby fluorine; or C(═NH)(NH₂), PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl,SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl,SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl, SO₂-(C₁-C₆)-alkyl, orSO₂—(CH₂)_(n)-phenyl, wherein n=0-6 and wherein the phenyl radical isunsubstituted or substituted one or two times, each substituent chosenindependently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, and NH₂; and NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,NHCO(C₁-C₆)-alkyl, phenyl, or O—(CH₂)_(n)-phenyl, wherein n=0-6, andwherein the phenyl ring is unsubstituted or substituted one, two, orthree times, each substituent chosen independently from: F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl,and CONH₂; wherein (LAG) is —(CH₂)₀₋₁₀—SO₃H; —(CH₂)₀₋₁₀—P(O)(OH)₂,—(CH₂)₀₋₁₀—O—P(O)(OH)₂, or —(CH₂)₀₋₁₀—COOH; wherein at least one of theradicals R1 or R3 must have the meaning: LAG; or(C₁-C₃₀)-alkylene-(LAG); or (C₁-C₃₀)-alkylene-(LAG), wherein at leastone carbon atom of the alkylene radical is replaced by —O—, —(C═O)—,—N(CH₃)— or —NH—.
 3. A compound as claimed in claim 1, wherein R2, R4,R5, and R6, independently of one another, are chosen from: H, F, Cl, Br,I, CF₃, NO₂, N₃, CN, COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl,CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, orO—(C₁-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at leastone hydrogen in the alkyl radical is replaced by fluorine; orC(═NH)(NH₂), PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl,SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl,SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl, SO₂—(C₁-C₆)-alkyl, orSO₂—(CH₂)_(n)-phenyl, wherein n=0-6 and wherein the phenyl radical isunsubstituted or substituted one or two times, each substituent chosenindependently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, and NH₂; and NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,NHCO(C₁-C₆)-alkyl, phenyl, or O—(CH₂)_(n)-phenyl, wherein n=0-6, andwherein the phenyl ring is unsubstituted or substituted one, two, orthree times, each substituent chosen independently from: F, Cl, Br, I,OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl,and CONH₂; R1 and R3, independently of one another, are chosen from:—(CH₂)₀₋₁—Y—W—Y′—W′-(LAG); or —(CH₂)₀₋₁—Y—W—(C₁C₂₅)-alkylene-Y′—W′-(LAG); or —(CH₂)₀₋₁—Y—W—(C₁C₂₅)-alkylene-Y′—W′-(LAG), wherein at least one carbon atom of thealkylene radical is replaced by —O—; or H, F, Cl, Br, I, CF₃, NO₂, N₃,CN, COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂,(C₁-C₆)-alkyl, (C₂—C₆)-alkenyl, (C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl,wherein the alkyl radical is unsubstituted or at least one hydrogen inthe alkyl radical is replaced by fluorine; or C(═NH)(NH₂), PO₃H₂, SO₃H,SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl,S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl,SO₂—(C₁-C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, wherein n=0-6, and whereinthe phenyl radical is unsubstituted or substituted one or two times,each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN,OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; and NH₂,NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NHCO(C₁-C₆)-alkyl, phenyl, orO—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl ring isunsubstituted or substituted one, two, or three times, each substituentchosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃,O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; wherein Y, W, Y′ W′,independently of one another, are chosen from: NH, NCH₃, C═O, O, a bond,and S(O)_(m), wherein m=0-2; or Y—W together represent a bond; or Y′—W′together represent a bond; and wherein (LAG) is chosen from:—(CH₂)₀₋₁₀—SO₃H, —(CH₂)₀₋₁₀—P(O)(OH)₂, (CH₂)₀₋₁₀—O—P(O)(OH)₂, and—(CH₂)₀₋₁₀—COOH; and wherein at least one of the radicals R1 or R3 musthave the meaning: —(CH₂)₀₋₁—Y—W—Y′—W′-(LAG); or (CH₂)₀₋₁—Y—W—(C₁C₂₅)-alkylene-Y′—W′-(LAG); or —(CH₂)₀₋₁—Y—W—(C₁C₂₅-alkylene-Y′—W′-(LAG); wherein at least one carbon atom of thealkylene radical is replaced by —O—.
 4. A compound as claimed in claim1, wherein (LAG) is —(CH₂)₀₋₁₀—COOH or —(CH₂)₀₋₁₀—SO₃H.
 5. Apharmaceutical composition, comprising an effective amount of at leastone compound as claimed in claim
 1. 6. A pharmaceutical composition,comprising an effective amount of at least one compound as claimed inclaim 1, and at least one additional active compound.
 7. Thepharmaceutical composition of claim 6, wherein the at least oneadditional active compound is chosen from compounds that normalize lipidmetabolism.
 8. The pharmaceutical composition of claim 6, wherein the atleast one additional active compound is chosen from antidiabetics,hypoglycemically active compounds, HMGCoA reductase inhibitors,cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alphaagonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acidabsorption inhibitors, CETP inhibitors, polymeric bile acid adsorbers,LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipaseinhibitors, ATP citrate lyase inhibitors, squalene synthetaseinhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins,sulfonylureas, biguanides, meglitinides, thiazolidinediones,α-glucosidase inhibitors, active compounds which act on theATP-dependent potassium channel of the beta cells, CART agonists, NPYagonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRFagonists, CRF BP antagonists, urocortin agonists, β3 agonists, MSH(melanocyte-stimulating hormone) agonists, CCK agonists,serotonin-reuptake inhibitors, mixed serotonin and noradrenergiccompounds, 5HT agonists, bombesin agonists, galanin antagonists, growthhormones, growth hormone-releasing compounds, TRH agonists, decouplingprotein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine,doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators orTR-β-agonists and amphetamines.
 9. A method for treating a patientafflicted with impaired lipid metabolism, comprising administering to apatient in need thereof an effective amount of at least one compound asclaimed in claim
 1. 10. A process for preparing a pharmaceuticalcomposition comprising at least one compound as claimed in claim 1,comprising mixing the at least one compound with a pharmaceuticallyacceptable carrier and bringing this mixture into a form suitable foradministration.
 11. A method for treating hyperlipidemia, comprisingadministering to a patient in need thereof an effective amount of atleast one compound as claimed in claim
 1. 12. A method for lowering theserum cholesterol concentration, comprising administering to a patientin need thereof an effective amount of at least one compound as claimedin claim
 1. 13. A method for treating arteriosclerotic manifestations,comprising administering to a patient in need thereof an effectiveamount of at least one compound as claimed in claim
 1. 14. A method fortreating a patient afflicted with insulin resistance, comprisingadministering to a patient in need thereof an effective amount of atleast one compound as claimed in claim 1.